Four p38 MAPK isoforms (alpha, beta, gamma and delta respectively) have been identified, each displaying a tissue-specific expression pattern. The p38 MAPK alpha and beta isoforms are ubiquitously expressed throughout the body and are found in many different cell types. The p38 MAPK alpha and beta isoforms are inhibited by certain previously described small molecule p38 MAPK inhibitors. Earlier generations of compounds were found to be highly toxic due to the ubiquitous expression pattern of these isoforms which resulted in off-target effects of the compounds. More recently, improved inhibitors have been identified that are highly selective for the p38 MAPK alpha and beta isoforms and demonstrate a wider safety margin.
Less is known about the p38 MAPK gamma and delta isoforms. These isoforms are expressed in specific tissues/cells (unlike the p38 alpha and p38 beta isoforms). The p38 MAPK-delta isoform is expressed more in the pancreas, testes, lung, small intestine and kidney. It is also abundant in macrophages and detectable in neutrophils, CD4+ T cells and endothelial cells (Shmueli, O. et al., Comptes Rendus Biologies, 2003, 326(10-11):1067-1072/Genecard; Smith, S. J. Br. J. Pharmacol., 2006, 149:393-404; Hale, K. K., J. Immunol., 1999, 162(7):4246-52; Wang, X. S. et al., J. Biol. Chem., 1997, 272(38):23668-23674.) Very little is known about the expression of p38 MAPK gamma although it is expressed more highly in brain, skeletal muscle and heart, as well as in lymphocytes and macrophages. (Shmueli, O. et al., Comptes Rendus Biologies, 2003, 326(10-11):1067-1072/Genecard; Hale, K. K., J. Immunol., 1999, 162(7):4246-52: Court, N. W. et al., J. Mol. Cell. Cardiol., 2002, 34(4):413-26; Mertens, S. et al., FEBS Lett., 1996, 383(3):273-6.)
Selective small molecule inhibitors of p38 MAPK gamma and delta isozymes are not currently available, although one existing compound, BIRB 796, is known to possess pan-isoform inhibitory activity. The p38 gamma and p38 delta inhibition is observed at higher concentrations of the compound than those required to inhibit p38 MAPK alpha, (Kuma, Y. J. Biol. Chem., 2005, 280:19472-19479). BIRB 796 also impaired the phosphorylation of p38 MAPKs or JNKs by the upstream kinase MKK6 or MKK4. Kuma discussed the possibility that the conformational change caused by the binding of the inhibitor to the MAPK may affect the structure of both its phosphorylation site and the docking site for the upstream activator, therefore impairing the phosphorylation of p38 MAPKs or JNKs.
p38 MAP kinase is believed to play a pivotal role in many of the signalling pathways that are involved in initiating and maintaining chronic, persistent inflammation in human disease, for example, severe asthma and COPD. There is now abundant literature that demonstrates that p38 MAP kinase is activated by a range of pro-inflammatory cytokines and that its activation results in the recruitment and release of further pro-inflammatory cytokines. Indeed, data from some clinical studies demonstrate beneficial changes occur in the disease state of patients during treatment with p38 MAP kinase inhibitors. For instance Smith describes the inhibitory effect of p38 MAP kinase inhibitors on TNFα (but not IL-8) release from human PBMCs (Smith, S. J. Br. J. Pharmacol, 2006, 149:393-404). Use of inhibitors of p38 MAP kinase in the treatment of COPD is also proposed. Small molecule inhibitors targeted to p38 MAPKα/β have proved to be effective in reducing various parameters of inflammation in cells and tissues obtained from patients with COPD who are generally corticosteroid insensitive (Smith, S. J. Br. J. Pharmacol., 2006, 149:393-404) and in vivo animal models (Underwood D. C. et al., Am. J. Physiol. Lung Cell. Mol. Physiol., 2000, 279:895-902; Nath, P. et al., Eur. J. Pharmacol., 2006, 544:160-167; Medicherla S. et al., J. Pharm. Exp. Ther., 2008, 324:921-929.).
Irusen and colleagues also suggested the possibility of involvement of p38 MAPK a/13 on corticosteroid insensitivity via reduction of binding affinity of glucocorticoid receptor (GR) in nuclei (Irusen, E. et al., J. Allergy Clin. Immunol., 2002, 109:649-657). Clinical experience with a range of p38 MAP kinase inhibitors, including AMG548, BIRB 796, VX702, SCIO469 and SCIO323 has also been described (Lee, M. R. and Dominguez, C., Current Med. Chem., 2005, 12:2979-2994.).
COPD is a condition in which the underlying inflammation is reported to be substantially resistant to the anti-inflammatory effects of inhaled corticosteroids. Consequently, a superior strategy for treating COPD would be to develop an intervention which has both inherent anti-inflammatory effects and the ability to increase the sensitivity of the lung tissues of COPD patients to inhaled corticosteroids. The recent publication of Mercado et al (Mercado N. et al, American Thoracic Society Abstract, 2007, A56) demonstrates that silencing p38 gamma has the potential to restore patient sensitivity to corticosteroids. Thus there may be a therapeutically significant dual benefit to the use of a p38 MAP kinase inhibitor for the treatment of COPD and severe asthma.
There is now a substantial body of evidence which strongly implicates the role of respiratory viral infections in initiating exacerbations in patients suffering from asthma and/or COPD. Exacerbations require an increase in treatment intensity to re-establish control of disease symptomology. If severe, exacerbations may well result in the hospitalisation or, at their most extreme, the death of patients.
The major obstacle hindering the utility of p38 MAP kinase inhibitors in the treatment of human chronic inflammatory diseases has been the toxicity observed in patients. This has been sufficiently severe to result in the withdrawal from clinical development of many of the compounds progressed, including all those specifically mentioned above. There remains a need to identify and develop new compounds that have improved therapeutic potential, in particular that are more efficacious, longer acting and/or less toxic at the relevant therapeutic dose. An objective of the present invention is to provide compounds which inhibit p38 MAP kinase with certain sub-type specificity, and that consequently show enhanced anti-inflammatory potential and/or anti-viral activity.
The compounds of the present disclosure possess profiles in therapeutically relevant in vitro systems that are consistent with a superior mode of action for treating inflammatory lung disease and in particular for treatment of the same by inhaled administration. The inhibitory effects of compounds versus HRV-16 replication and poly I:C induced ICAM-1 expression were also determined.